The primary objective of this project is to develop new agents for the treatment of cancers in children and young adults with an emphasis on a more rational, targeted approach of drug development based on the current understanding of the molecular pathogenesis of human cancers. New molecularly targeted agents that are undergoing clinical development for adult cancers will be applied to childhood cancers based on the mechanism of action of the drug and the importance of the target in childhood cancers. In addition, novel cytotoxic agents are undergoing clinical evaluation. Clinical trials are conducted as single site and multi-site trials. In addition, we are collaborating with the Children's Oncology Group (COG), the sarcoma cooperative group SARC, and the NF Clinical Trials Consortium in the development and conduct of trials. Clinical trials target refractory solid tumors such as Ewing sarcoma or rhabdomyosarcoma, and tumors with no known effective medical therapy such as alveolar soft part sarcoma or malignant peripheral nerve sheath tumors (MPNST). This work is performed through the Pharmacology and Experimental Therapeutics (PET) Section of the NCI POB. Examples of clinical trials ongoing and in development include: 1) Example of collaboration with the Children's Oncology Group (COG): Phase I trial of cabozantinib (XL184) for refractory solid tumors: Cabozantinib is a small molecule inhibitor of multiple receptor tyrosine kinases (RTK) including primarily MET, VEGFR2 and RET and to a lesser extent KIT and TIE-2. RET inhibition provided the rationale for our development of cabozantinib for pediatric medullary thyroid carcinoma (MTC). However, cabozantinib also targets RTKs that are overexpressed in a variety of pediatric cancers including, VEGFR2 in pediatric sarcomas, MET in osteosarcoma, glioma, and papillary thyroid carcinoma. We thus collaborated with the COG Phase I/Pilot Consortium in the development of cabozantinib in a phase I trial with an arm specifically for MTC and an arm for refractory solid tumors including brain tumors. This trial has completed enrollment and has achieved the primary objectives. Based on promising results with several objective responses and prolonged disease stabilization we developed a phase II trial of cabozantinib for several solid tumor strata in collaboration with the COG (Chair: Srivandana Akshintala, NYU, Vice Chair: Brigitte Widemann). 2) Example of collaboration with the sarcoma cooperative group SARC and with the DoD sponsored NF Clinical trials Consortium: The mTOR pathway is involved in the progression of human cancers and neurofibromatosis type 1 (NF1) related tumors, and clinical trials with mTOR inhibitors are ongoing for both patient populations. I directed a SARC coordinated multi-institutional clinical trial for patients with refractory sporadic or NF1 related malignant peripheral nerve sheath tumors (MPNST) with the mTOR inhibitor RAD001 in combination with the angiogenesis inhibitor bevacizumab. This trial received funding through a Department of Defense Clinical Trial Award. Based on preclinical work from Dr. Karen Cichowski's laboratory, we also developed a phase I/II clinical trial of the mTOR inhibitor sirolimus in combination with the HSP90 inhibitor ganetespib for adults with refractory sarcomas and MPNST (PI: AeRang Kim, Co-PI: Brigitte Widemann). This trial is also complete. Based on promising preclinical results, a phase II trial combining an mTOR inhibitor (dual TORC kinase inhibitor) with a MEK inhibitor will soon open for enrollment (PI: AeRang Kim, Co-PI: Brigitte Widemann). Close collaboration of SARC, the DOD sponsored NF Consortium, and investigators invested in developing effective therapies for MPNST has demonstrated that the timely conduct of histology specific trials is feasible. 3) Example of a clinical trial development translating CCR laboratory findings to the clinic: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood, with an annual incidence of 4-7 cases per million children under 15 years in the US. Patients with metastatic and recurrent disease are essentially incurable with a 5-year overall survival of less than 20%, and outcomes have only minimally improved over the past several decades. Targeting of the type-1 insulin-like growth factor receptor (IGF-1R) has shown promise in the treatment of pediatric sarcomas, with clinically meaningful responses in about 10% of patients in early phase trials. In RMS models, preclinical work at the CCR (Dr. Helman) has demonstrated that blockade of IGF-1R results in YES activation and that YES activation is associated with resistance to IGF-1R blockade. In addition, combination treatment blocking both IGF-1R and YES results in enhanced growth inhibition of RMS in vitro and in vivo. In collaboration with Drs. Helman and Heske, we developed a phase I/II clinical trial of a monoclonal antibody against IGF-1R combined with an agent targeting YES for patients with RMS. This trial is open for enrollment. In another example, based on promising preclinical studies, we are also currently developing an early clinical trial combining a bomodomain inhibitor with a topoisomerase II inhibitor directed at refractory solid tumors in children and young adults. This trial will be directed by Dr. Jack Shern (Assistant Clinical Investigator in the POB). 4) Example for collaboration with the NCI CCR Developmental Therapeutics Clinic: We are collaborating with Dr. Alice Chen by enrolling children with refractory cancers such as alveolar soft part sarcoma, on primarily adult clinical trials directed by her. Similarly, Dr. Chen will evaluate adult patients on Pediatric Oncology Branch trials. This ensures that children and adults with rare tumors get optimal access to targeted therapies. We are currently developing a pediatric-adult rare tumor protocol with the goal to perform in depth natural history studies in select rare tumors. The NCI POB and my Section have a leadership role in 2 NCI CCR Initiatives: The NCI CCR Rare Tumors Initiative (RTI) fosters focused collaborations between basic and clinical researchers at NCI (CCR and DCEG), as well as extramural investigators. The Rare Tumor Patient Engagement Network (RTPEN), supported by the Cancer Moonshot, aims to connect patients and investigators through shared infrastructure and networks, accelerate the understanding of rare tumors and develop clinical trials for rare tumors through these national and international collaborations of patients, advocates, clinicians, clinical and basic researchers, and other stakeholders. The long-term goal of the RTPEN is to effectively study the biology and clinical course of rare tumors, translate these findings to improve care and treatment and to ensure that all patients have access to clinical trials which may benefit them.